Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism.
The glycolytic inhibitor 2-deoxyglucose (2-DG) was tested as a potential chemotherapeutic agent for drug-resistant cancer cells. Previously it was found that Adriamycin-resistant human MCF-7 breast cancer cells (ADR) exhibit an enhanced rate of glycolysis compared to their parent wild-type (WT) cell line (R. C. Lyon et al., Cancer Res., 48: 870-877, 1987). We now describe a specific toxic effect of 2-DG on the ADR cells, which is more than 15-fold greater than for WT cells. Using 31P magnetic resonance spectroscopy of perfused MCF7 cells we continuously monitored the accumulation of 2-deoxyglucose 6-phosphate together with concomitant changes in other phosphate-containing metabolites. Kinetic measurements demonstrated that ADR cells accumulated 2-deoxyglucose 6-phosphate faster and to a greater extent than WT cells, while their depletion of high energy compounds (ATP, phosphocreatine) was more pronounced and became irreversible earlier. The phosphorylation of 2-DG could be followed more effectively by the use of 13C magnetic resonance spectroscopy of 2-DG enriched with 13C at C-6, since the signals of 2-DG and 2-deoxyglucose 6-phosphate are clearly resolved and, unlike 31P magnetic resonance spectroscopy, there are no other interfering signals. With the use of this technique with ADR and WT cells the rate of phosphorylation of 2-DG was found to be 11.2 x 10(-4) and 6.5 x 10(-4) mmol/min/mg protein, respectively. The results of these studies indicate that differences in the biochemistry of energy metabolism of resistant cells may make them targets for energy antimetabolites.
Kaplan
O
O
Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Navon
G
G
Lyon
R C
RC
Faustino
P J
PJ
Straka
E J
EJ
Cohen
J S
JS
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D003837:Deoxy Sugars / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004351:Drug Resistance; D004357:Drug Synergism; D006019:Glycolysis / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D003837:Deoxy Sugars; D010710:Phosphates; D004317:Doxorubicin; D003847:Deoxyglucose